tbuckley/cabot-search huggingface dataset:
Abstract 3087: The identification and characterization of FOLFOX chemotherapy resistant cell lineages in colorectal cancer organoids
Authors: Julia M. Morris, Curtis A. Thorne
Journal: Cancer Research (2022)

Abstract Resistance to chemotherapy drugs is a well-documented issue inhibiting the treatment of a wide variety of cancers. Colorectal cancer (CRC) is the third most common neoplasm worldwide and has the third highest mortality rate. However, the longtime gold-standard FOLFOX chemotherapy regimen, consisting of 5-FU and Oxaliplatin, results in only 70% survival rates in Stage 3 CRC patients, worse in Stage 4. More recent targeted therapies have marginally improved on this number, but the fact remains that CRC represents a highly heterogeneous neoplasm and resistance to standard chemotherapeutic regimens poses a significant barrier in treating this devastating disease. There is an immediate need to better understand how this resistance arises. We hypothesize that a small number of cells with high phenotypic plasticity (HPP) are able to remain dormant during the initial chemotherapy treatment then reenter the cell cycle to cause recurrence and metastasis months or even years after treatment has concluded. Patient-derived organoids (PDOs) are a recently developed ex vivo model that allows for the study and extensive characterization of such HPP cell populations that may be found in patient tumors. We are developing and expanding various PDO populations to examine them genotypically and phenotypically on the single-cell level through RNA sequencing and high throughput imaging, respectively. By identifying these HPP cell populations, we then discover drugs that prevent the development of drug-resistant subpopulations. In the long term, we use our tumor heterogeneity profile to develop models that predict the responsiveness of tumors, including their drug-resistant HPP subpopulations, to well-documented and clinically used oncology drugs, streamlining treatment and improving survival outcomes. Citation Format: Julia M. Morris, Curtis A. Thorne. The identification and characterization of FOLFOX chemotherapy resistant cell lineages in colorectal cancer organoids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3087.
Screening for CD19-specific chimaeric antigen receptors with enhanced signalling via a barcoded library of intracellular domains
Authors: Khloe S. Gordon, Taeyoon Kyung, Caleb R. Perez, Patrick V. Holec, Azucena Ramos, Angela Q. Zhang, Yash Agarwal, Yunpeng Liu, Catherine E. Koch, Alina Starchenko, Brian A. Joughin, Douglas A. Lauffenburger, Darrell J. Irvine, Michael T. Hemann, Michael E. Birnbaum
Journal: Nature Biomedical Engineering (2022)
Abstract 2866: BAY 3375968: An afucosylated anti-CCR8 antibody depleting activated intratumoral regulatory T cells as a cancer immunotherapy
Authors: Helge Roider, Su-Yi Tseng, Sabine Hoff, Sandra Berndt, Katharina Filarski, Uwe Gritzan, Beatrix Stelte-Ludwig, Wiebke M. Nadler, Joanna Grudzinska-Goebel, Philipp Ellinger, Mark Trautwein, Matyas Gorjanacz
Journal: Cancer Research (2022)

Abstract Regulatory T cells (Tregs) play an indispensable role in mediating peripheral tolerance to self-antigens. They can also promote tumor growth by suppressing the function of effector CD8+ and CD4+ T cells in the tumor microenvironment (TME). Furthermore, Tregs are identified as one of the key resistance mechanisms hampering the efficacy of immune checkpoint inhibitors (ICIs) across many tumor types. Therefore, there is a high need for safe and effective agents that would specifically deplete tumor-infiltrating Tregs while sparing both peripheral Tregs and effector T cells. Chemokine receptor 8 (CCR8) is predominantly expressed on activated tumor-infiltrating Tregs and marks the most suppressive and proliferative Treg population. CCR8+ Tregs are associated with high tumor grade and poor overall survival across many tumor types such as lung, breast, or head-neck cancer. Thus, unlike other approaches directed against Tregs, targeting CCR8 offers the opportunity to specifically deplete intra-tumoral Tregs without impacting peripheral Tregs or other immune cells. BAY 3375968 is a non-internalizing fully human glycoengineered (afucosylated) monoclonal IgG1 antibody, which in vitro selectively depleted human CCR8+ Tregs via antibody dependent cellular cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP). In vivo efficacy studies using mouse surrogate antibodies showed strong monotherapeutic efficacy across a variety of murine tumor models with clear correlation of intratumoral CCR8+ Treg depletion and CD8+ T cell increase. The monotherapeutic efficacy of CCR8 depleting antibodies was further enhanced by combinations with ICIs. BAY 3375968 also showed a good safety profile in cynomolgus monkeys. In conclusion, CCR8 is a novel Treg depleting immunotherapy target, and due to its highly tumor-restricted expression profile, BAY 3375968 may provide superior clinical safety and efficacy profile comparing to other less specific Treg targeting approaches. Based on the promising pre-clinical data, preparations for a phase I clinical trial investigating the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity of BAY 3375968 are underway. Citation Format: Helge Roider, Su-Yi Tseng, Sabine Hoff, Sandra Berndt, Katharina Filarski, Uwe Gritzan, Beatrix Stelte-Ludwig, Wiebke M. Nadler, Joanna Grudzinska-Goebel, Philipp Ellinger, Mark Trautwein, Matyas Gorjanacz. BAY 3375968: An afucosylated anti-CCR8 antibody depleting activated intratumoral regulatory T cells as a cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2866.
Abstract 3864: Cytometric analysis of immune cell populations in clinical tumor biopsy tissue microarrays for immuno-oncology
Authors: Tom Villani, Jigar Patel, Kim Collins, Kate Lillard Tunstall, Bradley Krisanits
Journal: Cancer Research (2022)

Abstract Over the past decade, a new focus on the interactions between the immune system and the development and progression of cancer has led to a wide array of research into medical treatments which leverage activation or modulation of the immune system to aid in treatment. Research in the field of immuno-oncology and elucidation of the biological mechanisms by which cancer cells suppress immunological function has led to new biological treatments for cancer, such as pembrolizumab, which have shown great clinical success since their advent. Population-level analysis of immune cell populations is critical for understanding the immune-component of disease progression, and flow cytometry is a commonly utilized technique for this purpose. However, flow cytometry requires dissolution of tissue specimens, and is incompatible with formalin-fixed paraffin-embedded (FFPE) samples, the gold standard in tissue archives. In order to allow for cytometric analysis of FFPE tissues, we have developed a digital pathology technique for the quantitative assessment of immune-cell populations within tissue microarrays prepared from archived FFPE clinical tissue specimens from patient biopsies. The technique involves a combination of HALO® image analysis using the Highplex FL, Spatial Analysis, and TMA modules, and custom scripting to develop imaging cytometry scatterplots. Bioinformatics techniques were utilized to assess features correlated with tumor progression from the quantitative data extracted from the tissue microarrays. Citation Format: Tom Villani, Jigar Patel, Kim Collins, Kate Lillard Tunstall, Bradley Krisanits. Cytometric analysis of immune cell populations in clinical tumor biopsy tissue microarrays for immuno-oncology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3864.
Abstract 1223: Accurate inference of genetic ancestry from cancer-derived data
Authors: Pascal Belleau, Astrid Deschênes, David A. Tuveson, Alexander Krasnitz
Journal: Cancer Research (2022)

Abstract Introduction: For multiple cancer types, epidemiological data exhibit strong correlations between, on the one hand, the incidence of the disease, its severity when diagnosed, and its clinical outcome, and, on the other hand, the ancestral background of the patient. Recent studies point to genetic and phenotypic differences between tumors in patient populations with differing genetic ancestries, and to the need for more data collection to power research in this area. We sought to facilitate such analysis by developing computational tools for genetic ancestry inference from cancer-derived molecular data, without the need for the patient’s cancer-free genotype or self-declared race or ethnicity. The ability to perform such inference accurately would unlock vast amounts of such data for ancestry-oriented studies of cancer from two major sources. One is the body of data stored by similar massive digital repositories. The other is the body of archival tumor tissues from which molecular data may be generated. Methods: We developed methods for genetic ancestry inference from cancer-derived whole exomes, transcriptomes and targeted gene panels, in the absence of matching cancer-free genomic data. These are adaptive, endowed with the ability to optimize their performance for each input cancer-derived molecular profile. As a result, these inference methods perform consistently, and with quantifiable accuracy, across a range of profiling depths and qualities, and mitigate cancer-related damage to the genome, such as somatic copy-number variation. Results: We examined the performance of these tools with molecular data from three cancer types: pancreatic and ovarian cancers as representative of epithelial tumor types, and acute myeloid leukemia as an example of hematopoietic malignancy. Three molecular data types were considered: whole-exome sequences, exome sequences targeting a panel of cancer-related genes and RNA sequences. The inference accuracy was found to be consistently above 97% across the three cancers and the three data types. Conclusion: Our study demonstrates the feasibility of accurate inference of genetic ancestry from cancer-derived data, with no need for matching cancer-free genotypes. Computational tools for this purpose will be made available as open-source software. Citation Format: Pascal Belleau, Astrid Deschênes, David A. Tuveson, Alexander Krasnitz. Accurate inference of genetic ancestry from cancer-derived data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1223.
Abstract 347: Comparative activity of MBQ-167 metabolites in metastatic breast cancer
Authors: Julia I. Medina, Eliud Hernández, Cornelis Vlaar, Suranganie Dharmawardhane
Journal: Cancer Research (2022)

Abstract Metastasis continues to be the most difficult phase for cancer treatment due to few targeted therapy options. Therefore, we focus on targeting the Rho GTPases Rac1 and Cdc42, key drivers of the primary steps of metastasis: cell migration and invasion. We developed MBQ-167 as a small molecule dual inhibitor for Rac1 and Cdc42 activation with IC50s of 103 and 78 nM, respectively. In metastatic human breast cancer cells, MBQ-167 inhibits the Rac/Cdc42 downstream effector p21-activated kinase (PAK)/LIM kinase/Cofilin signaling, lamellipodia extension, and thus, cell polarity, and migration. In addition, in metastatic breast cancer cells, MBQ-167 inhibits cell proliferation and cell cycle progression to ultimately induce apoptosis via anoikis. MBQ-167 inhibits tumor growth and metastasis in experimental and spontaneous HER-positive and Triple negative breast cancer (TNBC) mouse models. MBQ-167 has 35% bioavailability and is not toxic in rodent or canine models up to 1000 mg/kg. Therefore, we are further developing MBQ-167 as a lead anti metastatic cancer compound. The objective in this study is to elucidate potential activity of MBQ-167 metabolites. Prior work has identified MBQ-167 metabolites via LC MS/MS from a mammalian liver microsome (rats and human) assay. Four of the MBQ-167 metabolites with the highest MS peak area, were analyzed in metastatic breast cancer cell lines, for cell viability via MTT assays and apoptosis via caspase 3/7 assays. We report that the metabolites M6, M7, M8, and M9 did not inhibit cell viability or induce apoptosis at 250 or 500 nM in HER2-type MDA-MB-435, and TNBC MDA-MB-231 and MDA-MB-468 breast cancer cell lines, compared to MBQ-167. We next analyzed whether these metabolites could inhibit the activation of Rac and Cdc42 by analyzing the phosphorylation status of its downstream effector p-21 activated kinase isoforms 1/2/3 (PAK1/2/3). When MBQ-167 and metabolites at 250nM were incubated for 24h in HER2-type MDA-MB-435 metastatic cancer cells, and the lysates western blotted with antibodies to total PAK1/2/3 or phospho-Pak1/2/3, we found a decrease in the phosphorylation levels of PAK in response to MBQ-167 and metabolite M6. However, since the peak area of M6 in the microsome assay is only 6% compared to MBQ-167, we conclude that MBQ-167 is the major active compound with anti-metastatic cancer properties. Citation Format: Julia I. Medina, Eliud Hernández, Cornelis Vlaar, Suranganie Dharmawardhane. Comparative activity of MBQ-167 metabolites in metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 347.
Abstract 6206: Discerning vasculature destruction caused by novel vascular disrupting agents examined by optical and multispectral optoacoustic imaging
Authors: Hashini I. Wanniarachchi, Regan Schuetze, Lorena Arango, Khagendra Hamal, Graham J. Carlson, Cyprian Pavlich, Yuling Deng, Mary L. Trawick, Kevin G. Pinney, Li Liu, Ralph P. Mason
Journal: Cancer Research (2022)

Abstract Tumor growth requires a functioning vascular network and offers an attractive therapeutic target. The invasive proliferating neovasculature of tumors lacks pericyte support and exhibits increased permeability thereby offering a unique, potentially selective target for anticancer therapy. Most vascular disrupting agents (VDAs) inhibit microtubule formation, causing rapid morphological changes in endothelia cells resulting in dramatically increased vessel permeability, cellular detachment, vessel occlusion, and vessel wall damage [doi: 10.3390/molecules26092551]. Highly vascular kidney tumors are expected to be particularly sensitive to VDAs. We are evaluating OXi8007, a water soluble indole phosphate pro-drug derivative of the first generation VDA combretastatin. The prodrug OXi8007 is stable in saline but releases active OXi8006 is the presence of alkaline phosphate. Preliminary pharmacokinetic data benchmarked using 13C-labeled OXi8006 and OXi8007 show rapid vascular clearance and conversion to the glucuronide conjugate in vivo. Doses up to 700 mg/kg were tolerated by mice. Luciferase-expressing RENCA tumor cells were implanted orthotopically in the right kidney capsule of syngeneic BALB/c mice. Bioluminescence Imaging (BLI) was applied weekly to assess tumor growth and acute response to OXi8007. Following addition of luciferin substrate subcutaneously BLI signal from the tumor reached a maximum within 10 minutes. When BLI was repeated 4 hrs after 250 or 350 mg/kg OXi8007 IP, the generated signal was &amp;lt;1% of baseline signal indicating acute vascular disruption. Multispectral Optoacoustic Tomography (MSOT) revealed matching acute changes in tumor vascular oxygenation and additionally showed distinct heterogeneity. An oxygen gas breathing challenge indicated lower oxygen saturation in the tumor following treatment. Histology showed massive hemorrhage following both doses. BLI signal recovered after 1 to 2 days and repeated administration of OXi8007 again caused acute vascular shutdown. These results match previous observations in breast tumor models [doi: 10.1016/j.canlet.2015.08.021] indicating opportunities for therapeutic application. Citation Format: Hashini I. Wanniarachchi, Regan Schuetze, Lorena Arango, Khagendra Hamal, Graham J. Carlson, Cyprian Pavlich, Yuling Deng, Mary L. Trawick, Kevin G. Pinney, Li Liu, Ralph P. Mason. Discerning vasculature destruction caused by novel vascular disrupting agents examined by optical and multispectral optoacoustic imaging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6206.
Abstract 2377: Impairment of p53-activating pathways accelerates liver cancer initiation partially through MTHFD1L-mediated 1C metabolism
Authors: Yiwei Zhang, Yitian Zha, Hua Lu
Journal: Cancer Research (2022)

Abstract Hepatocellular carcinoma (HCC) takes several decades to develop from premalignant lesions in chronically damaged livers and is often detected at a later stage; thus, prevention is of particular importance. HCC originates from differentiated hepatocytes. Previous studies have shown that inhibition of the tumor suppressor p53 is required for the differentiated hepatocytes to acquire the features that are needed for their conversion to HCC progenitor cells (HcPCs). However, the initiation of p53 response to de-differentiation of damaged hepatocytes is largely unclear. p53 is tightly controlled by MDM2 and MDMX. We and others have previously demonstrated that multiple stresses can trigger the binding of 14-3-3 to phosphorylated MDMX, or ribosomal proteins L5 and L11 to MDM2, to further disrupt the MDMX- or MDM2-p53 association and lead to p53 activation. This was validated by two animal models, MDM2C305F and MDMX3SA knock-in mice that are defective in 14-3-3-MDMX and L5/L11-MDM2 interactions, respectively. By crossing these two mouse lines, we generated a double knock-in (DKI) mouse line. With this line, we found that carcinogen DEN-induced HCC occurrence is significantly higher in MDM2C305F-MDMX3SA -DKI mice, and HcPCs isolated from DEN-treated DKI mice display significantly more stem cell- and malignancy- properties and higher tumorigenesis when introduced into mouse livers. Furthermore, we found that MTHFD1L, a monofunctional tetrahydrofolate synthase required for mitochondrial 1-carbon (1C) metabolism, is transcriptionally suppressed by p53 and exerts a critical effect on the accelerated HCC initiation in DKI mice. Taken together, these results demonstrate a crucial role of these two p53-activating pathways in preventing HCC initiation by controlling the mitochondrial 1C- metabolism. Citation Format: Yiwei Zhang, Yitian Zha, Hua Lu. Impairment of p53-activating pathways accelerates liver cancer initiation partially through MTHFD1L-mediated 1C metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2377.
Abstract 2695: Transcriptomic profiling of human patients with acute myeloid leukemia reveals critical effects of growth hormone responsiveness on patient survival and mechanisms of tumor therapy resistance
Authors: Emily Davis, Reetobrata Basu, John J. Kopchick
Journal: Cancer Research (2022)

Abstract Growth hormone (GH) has been reported to drive leukemia cell proliferation as early as 1977, while downstream effectors of the GH signaling pathway (i.e., insulin-like growth factor 1; IGF1) have more recently been widely implicated in the aggressive pathology and robust therapy resistance phenotypes of acute myeloid leukemia (AML). It is also known that patients with acromegaly (high levels of circulating GH and IGF1) develop AML at a significantly higher rate than the general population, while individuals with GH resistance remain completely resistant to all types of cancer. Despite all of the aforementioned evidence pointing to a critical role of GH in AML progression and prognosis, a detailed transcriptomic analysis of human patients is lacking. We aim to address this gap by thorough in silico studies aimed at revealing the nature and extent to which the GH axis can be suitable targeted in AML. Here, we present a summary of our analyses of clinical and transcriptomic data from 200 human patients with AML from The Cancer Genome Atlas database, using multiple bioinformatics software programs in the public domain. Our study revealed that GH receptor (GHR) is expressed more highly in AML than in normal myeloid cells, and a robust correlation exists between GH responsiveness and patient survival. A sex-specific profiling of the patient transcriptomic data identified critical pathways related to therapy resistance, extracellular matrix remodeling, metastasis, and immune evasion to be upregulated differentially in male and female AML patients with relatively elevated GHR expression compared to patients with relatively lower GHR expression. Furthermore, we identified microRNAs which are differentially expressed in AML patients with higher than median GHR expression. We validated these miRNAs to be effective indicators of disease progression and prognosis and can be valuable markers in liquid biopsy approaches. Acknowledgement: This work was supported in part by the State of Ohio’s Eminent Scholar Program that includes a gift from Milton and Lawrence Goll, by the AMVETS, and Ohio University’s Edison Biotechnology Institute. Citation Format: Emily Davis, Reetobrata Basu, John J. Kopchick. Transcriptomic profiling of human patients with acute myeloid leukemia reveals critical effects of growth hormone responsiveness on patient survival and mechanisms of tumor therapy resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2695.